We are developing a platform technology that allows predictable, controlled release of drugs from macromolecule-drug conjugates. In one current format, PEG of sufficient size to have prolonged blood circulation times is attached to the drug by linkers designed to release the native drug at predictable and controlled rates. However, there are limitations to the use of PEG as the carrier of drugs via releasable linkers. First, using a PEG of MW e40,000 the drug payload is limited such that only very potent drugs are suitable. Second, whereas permanent PEGylation requires an attachment site of the drug that provides maximal activity, our linkers are optimally used when the connection silences activity;in either case, time-consuming SAR may be required to determine appropriate attachment sites to the drug. To overcome these limitations, we are proposing to develop PEGylated dendrimers as releasable carriers for therapeutic small molecules and peptides. Here, drugs will be attached via our releasable linkers to multiple surface residues of a dendrimer, and remaining surface residues will be attached to PEG;in effect, we will be immersing the drug in a layer of confined, concentrated PEG. The expected attributes of such PEGylated-dendrimer-drug conjugates include a) prolonged blood circulation times, b) protection of drugs against degradative enzymes, c) high capacity, d) controlled drug release, and e) inactivity against targets until released. ! PUBLIC HEALTH RELEVANCE: If the project is successful, we will have developed a novel, high-capacity carrier for drugs - small molecule and peptidic - that: a) prolongs blood circulation times of the drugs, b) protects them against degradation, c) silences their activity until released from the carrier, and d) allows predictable, controlled release of the active drug. The technology can be used to target many therapeutic targets, and we will focus on diabetes and cancer therapeutics. !